Apaf1 apoptotic function critically limits Sonic hedgehog signaling during craniofacial development

A. B. Long, William Kaiser, E. S. Mocarski, T. Caspary

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Apaf1 is an evolutionarily conserved component of the apoptosome. In mammals, the apoptosome assembles when cytochrome c is released from mitochondria, binding Apaf1 in an ATP-dependent manner and activating caspase 9 to execute apoptosis. Here we identify and characterize a novel mouse mutant, yautja, and find it results from a leucine-to-proline substitution in the winged-helix domain of Apaf1. We show that this allele of Apaf1 is unique, as the yautja mutant Apaf1 protein is stable, yet does not possess apoptotic function in cell culture or in vivo assays. Mutant embryos die perinatally with defects in craniofacial and nervous system development, as well as reduced levels of apoptosis. We further investigated the defects in craniofacial development in the yautja mutation and found altered Sonic hedgehog (Shh) signaling between the prechordal plate and the frontonasal ectoderm, leading to increased mesenchymal proliferation in the face and delayed or absent ossification of the skull base. Taken together, our data highlight the time-sensitive link between Shh signaling and the regulation of apoptosis function in craniofacial development to sculpt the face. We propose that decreased apoptosis in the developing nervous system allows Shh-producing cells to persist and direct a lateral outgrowth of the upper jaw, resulting in the craniofacial defects we see. Finally, the novel yautja Apaf1 allele offers the first in vivo understanding of a stable Apaf1 protein that lacks a function, which should make a useful tool with which to explore the regulation of programmed cell death in mammals.

Original languageEnglish (US)
Pages (from-to)1510-1520
Number of pages11
JournalCell Death and Differentiation
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

Fingerprint

Hedgehogs
Apoptosomes
Apoptosis
Nervous System
Mammals
Alleles
Ectoderm
Caspase 9
Skull Base
Maxilla
Mutant Proteins
Cytochromes c
Proline
Osteogenesis
Leucine
Mitochondria
Cell Death
Embryonic Structures
Cell Culture Techniques
Adenosine Triphosphate

Keywords

  • Apaf1
  • apoptosis
  • craniofacial development
  • programmed cell death
  • Shh signaling

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Apaf1 apoptotic function critically limits Sonic hedgehog signaling during craniofacial development. / Long, A. B.; Kaiser, William; Mocarski, E. S.; Caspary, T.

In: Cell Death and Differentiation, Vol. 20, No. 11, 01.11.2013, p. 1510-1520.

Research output: Contribution to journalArticle

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